The invention relates to new compounds of formula I, 
wherein the groups Ar, R1, R2, R3, R4 and X have the meanings given in the claims and specification, processes for preparing them as well as their use as pharmaceutical compositions, and the pharmaceutically acceptable salts thereof, processes for preparing them and pharmaceutical compositions containing these compounds. The compounds are valuable neurokinin (tachykinin) antagonists.
The compounds of formula I are partly covered by the broad general formula of International Patent Application WO96/32386. However, this does not disclose any compounds in which the amide group is substituted with a 2-phenyl-ethyl group and the piperidyl group in the 4 position is substituted with a substituted urethane or urea group. The compounds described in this international patent application are neurokinin antagonists with a broad spectrum of activity.
The problem of the present invention is to provide new neurokinin antagonists with an enhanced activity. This problem is now solved according to the invention by the preparation of the new compounds of formula I.
Surprisingly it has been found that the activity of the new NK1 receptor antagonists of formula I is dramatically increased compared with the known compounds.
The invention therefore relates to new compounds of formula I 
or the pharmaceutically acceptable salts thereof,
wherein
R1 denotes C1-C6-alkyl or Ar2,
R2 denotes hydrogen, C1-C6-alkyl or C3-C6-cycloalkylmethyl, or
R1 and R2 taken together denote a C2-C3-alkylenediyl group optionally substituted by one or two oxo groups (=O),
X denotes O or NR5,
Ar1 and Ar2 independently of one another denote unsubstituted phenyl or phenyl which is 1- to 5-substituted by halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy or xe2x80x94OCH2Oxe2x80x94;
R3 denotes 2-phenyl-ethyl, wherein the phenyl group may be substituted by 1 to 3 substituents, while the substituents, independently of one another, are selected from among halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy;
R4 denotes hydrogen, C1-C4-alkyl, C3-C8-cycloalkyl, CH2COOH, xe2x80x94CH2C(O)NH2, xe2x80x94OH or phenyl-C1-C4-alkyl; and
R5 denotes hydrogen or C1-C6-alkyl.
In the foregoing and in what is to follow, the terms xe2x80x9calkylxe2x80x9d and xe2x80x9calkoxyxe2x80x9d as used with reference to the groups R1, R2, R3, R4 or the substituents of Ar1 or Ar2 denote straight-chain or branched, saturated hydrocarbon groups with up to 6 carbon atoms, preferably 1 to 4 carbon atoms, particularly methyl, ethyl, n-propyl, 1-propyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy or i-propoxy.
In the foregoing and in what is to follow, the terms xe2x80x9cfluoroalkylxe2x80x9d and xe2x80x9cfluoroalkoxyxe2x80x9d as used with reference to the group R3 or the substituents of Ar denote straight-chain or branched, fluorine-substituted hydrocarbon groups with up to 4 carbon atoms and up to 9 fluorine atoms, preferably 1 or 2 carbon atoms and up to 5 fluorine atoms, particularly trifluoroethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy or 2-fluoroethoxy.
The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have substance P-antagonistic properties. They are useful for treating and preventing neurokinin-mediated illnesses and additionally have a dramatically increased effect.
Compounds of general formula I may have acid groups, mainly carboxyl groups, and/or basic groups such as, for example, amino functions. Compounds of general formula I may therefore be in the form of internal salts, salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or salts with pharmaceutically useable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as, for example, diethylamine, triethylamine, triethanolamine etc.
The compounds according to the invention may occur as racemates, or they may be obtained as pure enantiomers, i.e. in the (R)- or (S)-form. Compounds which occur as racemates or as the (S)-form are preferred.
The compounds according to the invention are valuable neurokinin (tachykinin) antagonists which have substance P-antagonistic properties. They are useful for treating and preventing neurokinin-mediated illnesses:
Treatment or prevention of inflammatory and allergic complaints of the airways, such as asthma, chronic bronchitis, hyperreactive airways, emphysema, rhinitis, COPD, pulmonary hypertension, cystic fibrosis, coughs;
of the eyes, such as conjunctivitis and iritis,
of the skin, such as dermatitis in contact eczema, neurodermatitis, pruritus, urticaria, psoriasis, sunburn, burns, insect bites, rosacea, itching, sensitive or hypersensitive skin, of the gastrointestinal tract, such as gastric and duodenal ulcers, ulcerative colitis, Crohn""s disease, inflammatory bowel disease, irritable colon, Hirschsprung""s disease, motility problems;
of the joints or bones, such as rheumatoid arthritis, reactive arthritis, arthrosis, osteoporosis and Reiter""s syndrome; of the bladder, such as irritable bladder, incontinence, urinary urgency, urethritis, colic and cystitis.
Also for the treatment of diseases of the central nervous system such as dementia, Alzheimer""s disease, schizophrenia, psychoses, anxiety states, alcohol or drug dependency, sexual dysfunctions, eating disorders, depression, headaches (e.g. migraine or tension headaches), epilepsy; Parkinson""s disease, stroke,
treatment of Herpes zoster as well as postherpetic pain, tumours, collagenoses, a dysfunction of the deferent urinary tracts, haemorrhoid, nausea and vomiting, triggered for example by radiation or cytostatic therapy or motion, and painful conditions of all kinds.
The invention therefore also relates to the use of the compounds of formula I as curative agents and pharmaceutical preparations which contain these compounds. They are preferably used on humans. The compounds according to the invention may be given intravenously, subcutaneously, intramuscularly, intraperitoneally, intranasally, by inhalation, transdermally, optionally assisted by iontophoresis or enhancers known from the literature, and by oral route.
For parenteral administration the compounds of formula I or their physiologically acceptable salts, may be put into solution, suspension or emulsion, possibly with substances conventionally used for this purpose such as solubilisers, emulsifiers or other adjuvants. Suitable solvents include, for example: water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerol, sugar solutions such as glucose or mannitol solutions or a mixture of various solvents.
In addition, the compounds may be administered by the use of implants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acid or intranasal preparations.
Compounds of formula I, wherein R4 denotes C1-C4-alkyl, particularly methyl, are preferred.
Also preferred are compounds of formula I wherein Ar is unsubstituted phenyl or 2,3-methylenedioxyphenyl, particularly unsubstituted phenyl.
Preferred compounds of formula I are those wherein R3 denotes 2-phenylethyl, wherein the phenyl group may be substituted by 1 to 3 substituents, wherein the substituents are selected independently of one another from among halogen, hydroxy, methyl, methoxy, trifluoromethyl, trifluoromethoxy, particularly wherein R3 is 2-(3,5-bis-trifluoromethylphenyl)-ethyl.
Particularly preferred compounds of formula I are those wherein the group xe2x80x94NR3R4 is 
In a preferred aspect the invention relates to compounds of formula I, wherein
R1 denotes a C1-C3-alkyl, particularly methyl, phenyl or C1-C3-alkoxyphenyl group, particularly 4-methoxyphenyl,
X denotes NH, and
R2 denotes a hydrogen atom.
In another preferred aspect the invention relates to compounds of formula I, wherein R1 and R2 taken together denote an ethylene-1,2-diyl, 1-oxoethylene-1,2-diyl, propylene-1,3-diyl, 1-oxopropylene-1,3-diyl or 1-oxobutylene-1,3-diyl group, and
X denotes O, NH or NCH3.
Particularly preferred are NK1 receptor antagonists of formula I, wherein the group
R1xe2x80x94Xxe2x80x94COxe2x80x94NR2xe2x80x94
is a group selected from the formulae A-1 to A-8: 
The following compounds are particularly preferred: 
The compounds may be prepared in a manner known per se.
Advantageous methods are illustrated and described in the following diagram. The compounds of general formula I may be prepared by reacting an
amide of formula II 
wherein X denotes a suitable leaving group, preferably halogen, alkylsulphonyloxy, particularly methylsulphonyloxy, or arylsulphonyloxy, particularly p-tolylsulphonyloxy,
with a piperidine of general formula III 
in an inert solvent in the presence of a base.
This process is illustrated by means of the following Diagram 1 for compounds wherein Ar is phenyl, R3 is bis-(trifluoromethyl)-phenylethyl and R4 is methyl. However, the process can be used analogously for all compounds of formula I. The compounds of formula III are known or may be prepared analogously to methods known per se.
Diagram 1
The reactant for this piperazine derivative is obtained as shown in Diagram 1, on the right. (R)-Mandelic acid is reacted with methanesulphonic acid halide to obtain (R)-2-(methanesulphonyloxy)-acetic acid. This is then reacted with a coupling reagent and the correspondingly substituted phenethylamine to obtain the corresponding amide, or it is converted into the corresponding acid halide (e.g. with SOCl2/SO2Cl2) and then converted with the suitably substituted phenethylamine into the corresponding amide. In the last step the amide thus obtained is reacted with the piperidine derivative described above, while during the substitution of methanesulphonate C-N-linking takes place with simultaneous reversal of the chiral centre. The reaction is carried out in an inert solvent, preferably a polar aprotic solvent such as, for example, DMF, dimethyl acetamide, ethylmethylketone or acetonitrile in the presence of a base, preferably an inorganic base such as, for example, K2CO3, NaHCO3 or CaCO3, or organic bases such as, for example, tertiary amines, preferably triethylamine, Hxc3xcnig base, pyridine or N-methylmorpholine, at between 0xc2x0 C. and 120xc2x0 C., typically between 10xc2x0 C. and 80xc2x0 C. The reaction time is generally between 0.5 h and 48 h.
The compounds and compositions according to the invention will now be illustrated by the Examples which follow. The skilled person is aware that the Examples serve only as an illustration and are not to be regarded as limiting.